Sex-specific associations of kynurenic acid with neopterin in Alzheimer's disease.

BACKGROUND: Sex differences in neuroinflammation could contribute to women's increased risk of Alzheimer's disease (AD), providing rationale for exploring sex-specific AD biomarkers. In AD, dysregulation of the kynurenine pathway (KP) contributes to neuroinflammation and there is some evidence of sex differences in KP metabolism. However, the sex-specific associations between KP metabolism and biomarkers of AD and neuroinflammation need to be explored further. METHODS: Here we investigate sex differences in cerebrospinal fluid concentrations of seven KP metabolites and sex-specific associations with established AD biomarkers and neopterin, an indicator of neuroinflammation. This study included 311 patients with symptomatic AD and 105 age-matched cognitively unimpaired (CU) controls, followed for up to 5 years. RESULTS: We found sex differences in KP metabolites in the AD group, with higher levels of most metabolites in men, while there were no sex differences in the CU group. In line with this, more KP metabolites were significantly altered in AD men compared to CU men, and there was a trend in the same direction in AD women. Furthermore, we found sex-specific associations between kynurenic acid and the kynurenic acid/quinolinic acid ratio with neopterin, but no sex differences in the associations between KP metabolites and clinical progression. DISCUSSION: In our cohort, sex differences in KP metabolites were restricted to AD patients. Our results suggest that dysregulation of the KP due to increased inflammation could contribute to higher AD risk in women.

Differences in metalloproteinases and their tissue inhibitors in the cerebrospinal fluid are associated with delirium.

BACKGROUND: The aetiology of delirium is not known, but pre-existing cognitive impairment is a predisposing factor. Here we explore the associations between delirium and cerebrospinal fluid (CSF) levels of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs), proteins with important roles in both acute injury and chronic neurodegeneration. METHODS: Using a 13-plex Discovery Assay®, we quantified CSF levels of 9 MMPs and 4 TIMPs in 280 hip fracture patients (140 with delirium), 107 cognitively unimpaired individuals, and 111 patients with Alzheimer's disease dementia. The two delirium-free control groups without acute trauma were included to unravel the effects of acute trauma (hip fracture), dementia, and delirium. RESULTS: Here we show that delirium is associated with higher levels of MMP-2, MMP-3, MMP-10, TIMP-1, and TIMP-2; a trend suggests lower levels of TIMP-4 are also associated with delirium. Most delirium patients had pre-existing dementia and low TIMP-4 is the only marker associated with delirium in adjusted analyses. MMP-2, MMP-12, and TIMP-1 levels are clearly higher in the hip fracture patients than in both control groups and several other MMP/TIMPs are impacted by acute trauma or dementia status. CONCLUSIONS: Several CSF MMP/TIMPs are significantly associated with delirium in hip fracture patients, but alterations in most of these MMP/TIMPs could likely be explained by acute trauma and/or pre-fracture dementia. Low levels of TIMP-4 appear to be directly associated with delirium, and the role of this marker in delirium pathophysiology should be further explored.

Delirium is a syndrome in which there are substantial changes in a person's ability to focus, understand, or pay attention to events. Delirium often occurs in response to sudden trauma and is more common in persons with pre-existing cognitive impairment. What happens in the brain during delirium is not well understood. To learn more, we have studied whether markers in the cerebrospinal fluid were altered in people with delirium compared to people without delirium. To understand differences specifically caused by delirium, we included two control groups without acute trauma, one with cognitively healthy participants and one with dementia patients. We found several markers altered in people with delirium, with most of the markers similarly altered in people with cognitive impairment due to dementia. One marker was directly linked to delirium and could potentially shed light on the brain processes that cause the syndrome.

Geriatric assessment with management for older patients with cancer receiving radiotherapy: a cluster-randomised controlled pilot study.

BACKGROUND: Geriatric assessment and management (GAM) improve outcomes in older patients with cancer treated with surgery or chemotherapy. It is unclear whether GAM may provide better function and quality of life (QoL), or be cost-effective, in a radiotherapy (RT) setting. METHODS: In this Norwegian cluster-randomised controlled pilot study, we assessed the impact of a GAM intervention involving specialist and primary health services. It was initiated in-hospital at the start of RT by assessing somatic and mental health, function, and social situation, followed by individually adapted management plans and systematic follow-up in the municipalities until 8 weeks after the end of RT, managed by municipal nurses as patients' care coordinators. Thirty-two municipal/city districts were 1:1 randomised to intervention or conventional care. Patients with cancer ≥ 65 years, referred for RT, were enrolled irrespective of cancer type, treatment intent, and frailty status, and followed the allocation of their residential district. The primary outcome was physical function measured by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (QLQ-C30). Secondary outcomes were overall quality of life (QoL), physical performance, use and costs of health services. Analyses followed the intention-to-treat principle. Study registration at ClinicalTrials.gov ID NCT03881137. RESULTS: We included 178 patients, 89 in each group with comparable age (mean 74.1), sex (female 38.2%), and Edmonton Frail Scale scores (mean 3.4 [scale 0-17], scores 0-3 [fit] in 57%). More intervention patients received curative RT (76.4 vs 61.8%), had higher irradiation doses (mean 54.1 vs 45.5 Gy), and longer lasting RT (mean 4.4 vs 3.6 weeks). The primary outcome was completed by 91% (intervention) vs 88% (control) of patients. No significant differences between groups on predefined outcomes were observed. GAM costs represented 3% of health service costs for the intervention group during the study period. CONCLUSIONS: In this heterogeneous cohort of older patients receiving RT, the majority was fit. We found no impact of the intervention on patient-centred outcomes or the cost of health services. Targeting a more homogeneous group of only pre-frail and frail patients is strongly recommended in future studies needed to clarify the role and organisation of GAM in RT settings.

Changes in sedentary behavior in the chronic phase following stroke.

BACKGROUND: Sedentary behavior increases risk for cardiovascular diseases. Little is known about sedentary behavior through the chronic phase after stroke. We aimed to describe how long and short bouts of sedentary behavior changed over the first three years after stroke and if cognition at baseline was an independent risk factor for sedentary behavior. METHODS: This is a sub-study of the Norwegian cognitive impairment after stroke (Nor-COAST) study, a multicenter study recruiting patients with acute stroke. Sedentary behavior was monitored with a thigh-worn sensor (ActivPal3®), at three-, 18- and 36-months post stroke. Stroke severity was assessed by National Institutes of Health Stroke Scale (NIHSS) and cognition by Montreal cognitive assessment (MoCA). Mixed model analysis with mean number of sedentary minutes accumulated daily as the dependent variable was repeated for all four zones (<30min, 30-60min, 60-90min, >90min) and for total sedentary time. RESULTS: The number of included participants was 528 (mean age 71.4, NIHSS on day 1, 2.7). The total amount of sedentary time accumulated between 08.00-22.00 increased significantly from about 9.8 hours at three months to 10.1 hours at 36 months post stroke (p=0.002). Patient characteristics associated with prolonged duration of the sedentary bouts and sedentary time were age, high BMI, comorbidities, and impaired physical function. No significant associations between MoCA score and sedentary time were found. CONCLUSION: The participants became increasingly sedentary and had fewer breaks in sedentary time from three to 36 months after stroke. Baseline cognition was not related to later sedentary behavior.

Genetic associations with psychosis and affective disturbance in Alzheimer's disease.

INTRODUCTION: Individuals with Alzheimer's disease (AD) commonly experience neuropsychiatric symptoms of psychosis (AD+P) and/or affective disturbance (depression, anxiety, and/or irritability, AD+A). This study's goal was to identify the genetic architecture of AD+P and AD+A, as well as their genetically correlated phenotypes. METHODS: Genome-wide association meta-analysis of 9988 AD participants from six source studies with participants characterized for AD+P AD+A, and a joint phenotype (AD+A+P). RESULTS: AD+P and AD+A were genetically correlated. However, AD+P and AD+A diverged in their genetic correlations with psychiatric phenotypes in individuals without AD. AD+P was negatively genetically correlated with bipolar disorder and positively with depressive symptoms. AD+A was positively correlated with anxiety disorder and more strongly correlated than AD+P with depressive symptoms. AD+P and AD+A+P had significant estimated heritability, whereas AD+A did not. Examination of the loci most strongly associated with the three phenotypes revealed overlapping and unique associations. DISCUSSION: AD+P, AD+A, and AD+A+P have both shared and divergent genetic associations pointing to the importance of incorporating genetic insights into future treatment development. Highlights: It has long been known that psychotic and affective symptoms are often comorbid in individuals diagnosed with Alzheimer's disease. Here we examined for the first time the genetic architecture underlying this clinical observation, determining that psychotic and affective phenotypes in Alzheimer's disease are genetically correlated.Nevertheless, psychotic and affective phenotypes in Alzheimer's disease diverged in their genetic correlations with psychiatric phenotypes assessed in individuals without Alzheimer's disease. Psychosis in Alzheimer's disease was negatively genetically correlated with bipolar disorder and positively with depressive symptoms, whereas the affective phenotypes in Alzheimer's disease were positively correlated with anxiety disorder and more strongly correlated than psychosis with depressive symptoms.Psychosis in Alzheimer's disease, and the joint psychotic and affective phenotype, had significant estimated heritability, whereas the affective in AD did not.Examination of the loci most strongly associated with the psychotic, affective, or joint phenotypes revealed overlapping and unique associations.

Neopterin, kynurenine metabolites, and indexes related to vitamin B6 are associated with post-stroke cognitive impairment: The Nor-COAST study.

BACKGROUND AND AIMS: We have previously shown that systemic inflammation was associated with post-stroke cognitive impairment (PSCI). Because neopterin, kynurenine pathway (KP) metabolites, and B6 vitamers are linked to inflammation, in our study we investigated whether those biomarkers were associated with PSCI. MATERIAL AND METHODS: The Norwegian Cognitive Impairment After Stroke study is a prospective multicenter cohort study of patients with acute stroke recruited from May 2015 through March 2017. Plasma samples of 422 participants (59 % male) with ischemic stroke from the index hospital stay and 3 months post-stroke were available for analyses of neopterin, KP metabolites, and B6 vitamers using liquid chromatography-tandem mass spectrometry. Mixed linear regression analyses adjusted for age, sex, and creatinine, were used to assess whether there were associations between those biomarkers and cognitive outcomes, measured by the Montreal Cognitive Assessment scale (MoCA) at 3-, 18-, and 36-month follow-up. RESULTS: Participants had a mean (SD) age of 72 (12) years, with a mean (SD) National Institutes of HealthStroke Scale score of 2.7 (3.6) at Day 1. Higher baseline values of quinolinic acid, PAr (i.e., an inflammatory marker based on vitamin B6 metabolites), and HKr (i.e., a marker of functional vitamin B6 status based on selected KP metabolites) were associated with lower MoCA score at 3, 18, and 36 months post-stroke (p < 0.01). Higher baseline concentrations of neopterin and 3-hydroxykynurenine were associated with lower MoCA scores at 18 and 36 months, and higher concentrations of xanthurenic acid were associated with higher MoCA score at 36 months (p < 0.01). At 3 months post-stroke, higher concentrations of neopterin and lower values of pyridoxal 5́-phosphate were associated with lower MoCA scores at 18- and 36-month follow-up, while lower concentrations of picolinic acid were associated with a lower MoCA score at 36 months (p < 0.01). CONCLUSION: Biomarkers and metabolites of systemic inflammation, including biomarkers of cellular immune activation, indexes of vitamin B6 homeostasis, and several neuroactive metabolites of the KP pathway, were associated with PSCI. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02650531.

Delirium in acute stroke is associated with increased cognitive and psychiatric symptoms over time: The Nor-COAST study.

BACKGROUND: Delirium, an acute and fluctuating mental disturbance of attention, cognition, and consciousness, commonly occurs in acute stroke. Research on long-term outcomes of stroke patients experiencing delirium is limited, especially regarding cognitive and psychiatric symptoms. METHODS: As part of the Nor-COAST study, 373 patients were screened for delirium using the Confusion Assessment Method (CAM) in the acute phase of stroke. Patients were included in the mixed-model linear regression analyses if they had available data from the follow-ups at three, 18 or 36 months, totaling 334 (44.6 % women, mean (SD) age: 72.1 (12.5) years, 17 (5.1 %) diagnosed with delirium). Global cognition was measured using the Montreal Cognitive Assessment (MoCA). Psychiatric symptoms were measured using the Hospital Anxiety and Depression Scale (HADS) and the Neuropsychiatric Inventory-Questionnaire (NPI-Q). RESULTS: At three months, delirium was associated with a higher NPI-Q score (Mean (SD) 2.9 (3.6) vs 1.4 (2.2)). At 18 and 36 months, delirium was associated with a lower MoCA score (Mean (SD) 19.7 (6.6) vs 24.3 (5.0), and 20.6 (7.6) vs 24.6 (4.8)), higher HADS anxiety symptoms (5.0 (4.3) vs 3.3 (3.3), and 5.9 (4.1) vs 3.4 (3.6)), higher HADS depression symptoms (7.2 (4.7) vs 3.4 (3.3), and 6.6 (5.1) vs 3.7 (3.7)), and higher NPI-Q score (2.4 (4.4) vs 1.7 (2.3), 2.6 (4.5) vs 1.0 (1.9)). Delirium significantly predicted the psychiatric symptoms hallucinations and agitation. CONCLUSIONS: Patients with delirium in the acute phase of stroke may be particularly vulnerable to developing cognitive and psychiatric symptoms in the chronic phase.

A Machine Learning Approach to Predict Post-stroke Fatigue. The Nor-COAST study.

OBJECTIVE: This study aimed to predict fatigue 18 months post-stroke by utilizing comprehensive data from the acute and sub-acute phases after stroke in a machine-learning set-up. DESIGN: A prospective multicenter cohort-study with 18-month follow-up. SETTING: Outpatient clinics at 3 university hospitals and 2 local hospitals. PARTICIPANTS: 474 participants with the diagnosis of acute stroke (mean ± SD age; 70.5 (11.3), 59% male; N=474). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The primary outcome, fatigue at 18 months, was assessed using the Fatigue Severity Scale (FSS-7). FSS-7≥5 was defined as fatigue. In total, 45 prediction variables were collected, at initial hospital-stay and 3-month post-stroke. RESULTS: The best performing model, random forest, predicted 69% of all subjects with fatigue correctly with a sensitivity of 0.69 (95% CI: 0.50, 0.86), a specificity of 0.74 (95% CI: 0.66, 0.83), and an Area under the Receiver Operator Characteristic curve of 0.79 (95% CI: 0.69, 0.87) in new unseen data. The proportion of subjects predicted to suffer from fatigue, who truly suffered from fatigue at 18-months was estimated to 0.41 (95% CI: 0.26, 0.57). The proportion of subjects predicted to be free from fatigue who truly did not have fatigue at 18-months was estimated to 0.90 (95% CI: 0.83, 0.96). CONCLUSIONS: Our findings indicate that the model has satisfactory ability to predict fatigue in the chronic phase post-stroke and may be applicable in clinical settings.

Diagnostic accuracy of the Clock Drawing Test in screening for early post-stroke neurocognitive disorder: the Nor-COAST study.

BACKGROUND: Post-stroke neurocognitive disorder, though common, is often overlooked by clinicians. Moreover, although the Montreal Cognitive Assessment (MoCA) has proven to be a valid screening test for neurocognitive disorder, even more time saving tests would be preferred. In our study, we aimed to determine the diagnostic accuracy of the Clock Drawing Test (CDT) for post-stroke neurocognitive disorder and the association between the CDT and MoCA. METHODS: This study is part of the Norwegian Cognitive Impairment After Stroke study, a multicentre prospective cohort study following patients admitted with acute stroke. At the three-month follow-up, patients were classified with normal cognition, mild neurocognitive disorder, or major neurocognitive disorder according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria. Any neurocognitive disorder compromised both mild- and major neurocognitive disorder. The CDT at the three-month assessment was given scores ranging from 0 to 5. Patients able to complete the CDT and whose cognitive status could be classified were included in analyses. The CDT diagnostic accuracy for post-stroke neurocognitive disorder was identified using receiver operating characteristic curves, sensitivity, specificity, positive predictive value, and negative predictive value. The association between the MoCA and CDT was analysed with Spearman's rho. RESULTS: Of 554 participants, 238 (43.0%) were women. Mean (SD) age was 71.5 (11.8) years, while mean (SD) National Institutes of Health Stroke Scale score was 2.6 (3.7). The area under the receiver operating characteristic curve of the CDT for major neurocognitive disorder and any neurocognitive disorder was 0.73 (95% CI, 0.68-0.79) and 0.68 (95% CI, 0.63-0.72), respectively. A CDT cutoff of < 5 yielded 68% sensitivity and 60% specificity for any neurocognitive disorder and 78% sensitivity and 53% specificity for major neurocognitive disorder. Spearman's correlation coefficient between scores on the MoCA and CDT was 0.50 (95% CI, 0.44-0.57, p < .001). CONCLUSIONS: The CDT is not accurate enough to diagnose post-stroke neurocognitive disorder but shows acceptable accuracy in identifying major neurocognitive disorder. Performance on the CDT was associated with performance on MoCA; however, the CDT is inferior to MoCA in identifying post-stroke neurocognitive disorder. TRIAL REGISTRATION: ClinicalTrials.gov (NCT02650531). Retrospectively registered January 8, 2016.

Physical Activity Behavior and Its Association With Global Cognitive Function Three Months After Stroke: The Nor-COAST Study†.

OBJECTIVE: The purposes of this study were to determine the association between physical activity (PA) behavior and global cognitive function 3 months after stroke and to explore the role of physical capacity as a mediating factor. METHODS: Participants with stroke were successively recruited at 5 different hospitals in Norway. PA was measured using accelerometers, with a follow-up period of 7 consecutive days, and global cognitive function was assessed using the Montreal Cognitive Assessment (MoCA). The general pattern of PA and the percentage of participants adhering to World Health Organization PA recommendations (at least 150 minutes of moderate-intensity aerobic PA per week) were investigated using descriptive statistics. Multiple regression and mediator analyses were used to examine the relationship between PA behavior and MoCA scores; physical capacity, measured with the Short Physical Performance Battery, served as the mediating variable. RESULTS: A total of 193 women (42.6%) and 260 men (57.4%) with a median age of 73.7 years (25th and 75th percentiles = 65.8 and 80.4, respectively) and a median MoCA score of 25 points (25th and 75th percentiles = 22 and 27, respectively) were included. Mean total time spent walking at moderate intensity was 251.7 (SD = 164.6) min/wk (mean bout length = 20.9 [SD = 7.3] seconds), which indicated 69.3% adherence to World Health Organization guidelines. With each point decrease in the MoCA score, there was an expected 8.6% increase in the odds of nonadherence to PA recommendations. Physical capacity was identified as an important mediating factor, explaining the strength of the association between cognition and PA behavior. CONCLUSIONS: In contrast to previous research, in the present study, most participants adhered to the updated global PA guidelines. However, people who had survived stroke and had reduced cognitive function were at higher risk of inactivity, an association mediated by physical capacity. IMPACT: A better understanding of the association between cognition and PA behavior after stroke might help for developing more targeted early-onset interventions.

Higher concentrations of kynurenic acid in CSF are associated with the slower clinical progression of Alzheimer's disease.

INTRODUCTION: The kynurenine pathway's (KP) malfunction is closely related to Alzheimer's disease (AD), for antagonistic kynurenic acid (KA) and agonistic quinolinic acid act on the N-methyl-D-aspartate receptor, a possible therapeutic target in treating AD. METHODS: In our longitudinal case-control study, KP metabolites in the cerebrospinal fluid were analyzed in 311 patients with AD and 105 cognitively unimpaired controls. RESULTS: Patients with AD exhibited higher concentrations of KA (ß = 0.18, P < 0.01) and picolinic acid (ß = 0.20, P < 0.01) than the controls. KA was positively associated with tau pathology (ß = 0.29, P < 0.01), and a higher concentration of KA was associated with the slower progression of dementia. DISCUSSION: The higher concentrations of neuroprotective metabolites KA and picolinic acid suggest that the activation of the KP's neuroprotective branch is an adaptive response in AD and may be a promising target for intervention and treatment. Highlights Patients with Alzheimer's disease (AD) exhibited higher concentrations of kynurenic acid and picolinic acid than controls. Higher concentrations of kynurenic acid were associated with slower progression of AD. Potential neurotoxic kynurenines were not increased among patients with AD. Activation of the kynurenine pathway's neuroprotective branch may be an adaptive response in AD.

Multimodal individualised intervention to prevent functional decline after stroke: protocol of a randomised controlled trial on long-term follow-up after stroke (LAST-long).

INTRODUCTION: Multimodal interventions have emerged as new approaches to provide more targeted intervention to reduce functional decline after stroke. Still, the evidence is contradictory. The main objective of the Life After Stroke (LAST)-long trial is to investigate if monthly meetings with a stroke coordinator who offers a multimodal approach to long-term follow-up can prevent functional decline after stroke. METHODS AND ANALYSIS: LAST-long is a pragmatic single-blinded, parallel-group randomised controlled trial recruiting participants living in six different municipalities, admitted to four hospitals in Norway. The patients are screened for inclusion and recruited into the trial 3 months after stroke. A total of 300 patients fulfilling the inclusion criteria will be randomised to an intervention group receiving monthly follow-up by a community-based stroke coordinator who identifies the participants' individual risk profile and sets up an action plan based on individual goals, or to a control group receiving standard care. All participants undergo blinded assessments at 6-month, 12-month and 18-month follow-up. Modified Rankin Scale at 18 months is primary outcome. Secondary outcomes are results of blood tests, blood pressure, adherence to secondary prophylaxis, measures of activities of daily living, cognitive function, physical function, physical activity, patient reported outcome measures, caregiver's burden, the use and costs of health services, safety measures and measures of adherence to the intervention. Mixed models will be used to evaluate differences between the intervention and control group for all endpoints across the four time points, with treatment group, time as categorical covariates and their interaction as fixed effects, and patient as random effect. ETHICS AND DISSEMINATION: This trial was approved by the Regional Committee of Medical and Health Research Ethics, REC no. 2018/1809. The main results will be published in international peer-reviewed open access scientific journals and to policy-makers and end users in relevant channels. TRIAL REGISTRATION NUMBER: ClincalTrials.gov Identifier: NCT03859063, registered on 1 March 2019.

Sex-specific associations of matrix metalloproteinases in Alzheimer's disease.

INTRODUCTION: Alzheimer's disease (AD) can be characterised in vivo by biomarkers reflecting amyloid-ß (Aß) and tau pathology. However, there is a need for biomarkers reflecting additional pathological pathways. Matrix metalloproteinases (MMPs) have recently been highlighted as candidate biomarkers for sex-specific mechanisms and progression in AD. METHODS: In this cross-sectional study, we investigated nine MMPs and four tissue inhibitors of metalloproteinases (TIMPs) in the cerebrospinal fluid of 256 memory clinic patients with mild cognitive impairment or dementia due to AD and 100 cognitively unimpaired age-matched controls. We studied group differences in MMP/TIMP levels and examined the associations with established markers of Aß and tau pathology as well as disease progression. Further, we studied sex-specific interactions. RESULTS: MMP-10 and TIMP-2 levels differed significantly between the memory clinic patients and the cognitively unimpaired controls. Furthermore, MMP- and TIMP-levels were generally strongly associated with tau biomarkers, whereas only MMP-3 and TIMP-4 were associated with Aß biomarkers; these associations were sex-specific. In terms of progression, we found a trend towards higher MMP-10 at baseline predicting more cognitive and functional decline over time exclusively in women. CONCLUSION: Our results support the use of MMPs/TIMPs as markers of sex differences and progression in AD. Our findings show sex-specific effects of MMP-3 and TIMP-4 on amyloid pathology. Further, this study highlights that the sex-specific effects of MMP-10 on cognitive and functional decline should be studied further if MMP-10 is to be used as a prognostic biomarker for AD.

The impact of cognitive function on physical activity, physical function and quality of life in older adults following a hip fracture.

OBJECTIVE: To determine the impact of cognitive function on physical activity (PA), physical function and health-related quality of life (HRQoL) in older adults within the first year after hip fracture (HF) surgery. METHODS: We included 397 home-dwelling individuals aged 70 years or older with the ability to walk 10 m before the fracture. Cognitive function was measured at 1 month and other outcomes were assessed at 1, 4 and 12 months postoperatively. Mini-Mental State Examination was used to assess cognitive function, accelerometer-based body-worn sensors to register PA, Short Physical Performance Battery to test physical function and EuroQol-5-dimension-3-level to estimate the HRQoL. Data were analysed by linear mixed-effects models with interactions and ordinal logistic regression models. RESULTS: Cognitive function, adjusted for the pre-fracture ability to perform activities of daily living, comorbidity, age and gender, had an impact on PA [b = 3.64, 95% confidence interval (CI): 2.20-5.23, P < 0.001] and physical function (b = 0.08, 95% CI: 0.04-0.11, P < 0.001; b = 0.12, 95% CI: 0.09-0.15, P < 0.001; and b = 0.14, 95% CI: 0.10-0.18, P < 0.001 at 1, 4 and 12 months, respectively). The cognitive function did not have a considerable impact on HRQoL. CONCLUSIONS: For older adults with HFs, cognitive function 1 month postoperatively had a significant impact on PA and physical function in the first postoperative year. For the HRQoL, little or no evidence of such an effect was found.

Plasma Inflammatory Biomarkers Are Associated With Poststroke Cognitive Impairment: The Nor-COAST Study.

BACKGROUND: Inflammation is proposed to be involved in the pathogenesis of poststroke cognitive impairment. The aim of this study was to investigate associations between concentrations of systemic inflammatory biomarkers after ischemic stroke and poststroke cognitive impairment. METHODS: The Nor-COAST study (Norwegian Cognitive Impairment After Stroke) is a prospective observational multicenter cohort study, including patients hospitalized with acute stroke between 2015 and 2017. Inflammatory biomarkers, including the TCC (terminal C5b-9 complement complex) and 20 cytokines, were analyzed in plasma, collected at baseline, 3-, and 18 months poststroke, using ELISA and a multiplex assay. Global cognitive outcome was assessed with the Montreal Cognitive Assessment (MoCA) scale. We investigated the associations between plasma inflammatory biomarkers at baseline and MoCA score at 3-, 18-, and 36-month follow-ups; the associations between inflammatory biomarkers at 3 months and MoCA score at 18- and 36-month follow-ups; and the association between these biomarkers at 18 months and MoCA score at 36-month follow-up. We used mixed linear regression adjusted for age and sex. RESULTS: We included 455 survivors of ischemic stroke. Higher concentrations of 7 baseline biomarkers were significantly associated with lower MoCA score at 36 months; TCC, IL (interleukin)-6, and MIP (macrophage inflammatory protein)-1α were associated with MoCA at 3, 18, and 36 months (P<0.01). No biomarker at 3 months was significantly associated with MoCA score at either 18 or 36 months, whereas higher concentrations of 3 biomarkers at 18 months were associated with lower MoCA score at 36 months (P<0.01). TCC at baseline and IL-6 and MIP-1α measured both at baseline and 18 months were particularly strongly associated with MoCA (P<0.01). CONCLUSIONS: Higher concentrations of plasma inflammatory biomarkers were associated with lower MoCA scores up to 36 months poststroke. This was most pronounced for inflammatory biomarkers measured in the acute phase following stroke. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02650531.

Edmonton Frail Scale predicts mortality in older patients with cancer undergoing radiotherapy-A prospective observational study.

BACKGROUND: Several screening tools are developed to identify frailty in the increasing number of older patients with cancer. Edmonton Frail Scale (EFS) performs well in geriatric settings but is less studied in oncology. We aimed to investigate if EFS score (continuous and categorical) predicts survival in patients referred for radiotherapy, and to assess the concurrent validity of EFS compared with a modified geriatric assessment (mGA). METHODS: Prospective observational, single-center study including patients ≥65 years, referred for curative or palliative radiotherapy for confirmed cancer. Patients underwent mGA (assessment of cognition, mobility, falls, comorbidity, polypharmacy, depression, nutrition, and activities of daily living) and screening with EFS prior to radiotherapy. The predictive value of EFS score of two-year overall survival (OS) was assessed by Kaplan-Meier plots and compared by log-rank test. Cox proportional hazards regression model was estimated to adjust the associations for major cancer-related factors. Concurrent validity of EFS in relation to mGA was estimated by Spearman`s correlation coefficient and ordinal regression. Sensitivity and specificity for different cut-offs was assessed. RESULTS: Patients' (n = 301) mean age was 73.6 (SD 6.3) years, 159 (52.8%) were men, 54% received curative-intent treatment, breast cancer (32%) was the most prevalent diagnosis. According to EFS≥6, 101 (33.7%) were classified as frail. EFS score was predictive of OS [hazard ratio (HR) 1.20 (95% confidence interval (CI) 1.10-1.30)], as was increasing severity assessed by categorical EFS (p<0.001). There was a strong correlation between EFS score and number of geriatric impairments (Spearman`s correlation coefficient 0.77). EFS cut-off ≥6 had a sensitivity of 0.97 and specificity of 0.57 for identifying patients with minimum two geriatric impairments. CONCLUSION: EFS predicts mortality in older patients with cancer receiving radiotherapy, and it is a quick (<5 minutes) and sensitive screening tool to identify patients who may benefit from a geriatric assessment.

Longitudinal trajectories of functional recovery after hip fracture.

BACKGROUND: There is limited evidence regarding predictors of functional trajectories after hip fracture. We aimed to identify groups with different trajectories of functional recovery the first year after hip fracture, and to determine predictors for belonging to such groups. METHODS: This longitudinal study combined data from two large randomized controlled trials including patients with hip fracture. Participants were assessed at baseline, four and 12 months. We used the Nottingham Extended Activities of Daily Living (NEADL) as a measure of instrumental ADL (iADL) and Barthel Index for personal ADL (pADL). A growth mixture model was estimated to identify groups of patients following distinct trajectories of functioning. Baseline characteristics potentially predicting group-belonging were assessed by multiple nominal regression. RESULTS: Among 726 participants (mean age 83.0; 74.7% women), we identified four groups of patients following distinct ADL trajectories. None of the groups regained their pre-fracture ADL. For one of the groups identified in both ADL outcomes, a steep decline in function was shown the first four months after surgery, and none of the groups showed functional recovery between four and 12 months after surgery. CONCLUSIONS: No groups regained their pre-fracture ADL. Some of the patients with relatively high pre-fracture function, had a steep ADL decline. For this group there is a potential for recovery, but more knowledge and research is needed in this group. These findings could be useful in uncovering groups of patients with different functioning after a hip fracture, and aid in discharge planning.

Longitudinal brain age prediction and cognitive function after stroke.

Advanced age is associated with post-stroke cognitive decline. Machine learning based on brain scans can be used to estimate brain age of patients, and the corresponding difference from chronological age, the brain age gap (BAG), has been investigated in a range of clinical conditions, yet not thoroughly in post-stroke neurocognitive disorder (NCD). We aimed to investigate the association between BAG and post-stroke NCD over time. Lower BAG (younger appearing brain compared to chronological age) was found associated with lower risk of post-stroke NCD up to 36 months after stroke, even among those showing no evidence of impairments 3 months after hospital admission. For patients with no NCD at baseline, survival analysis suggested that higher baseline BAG was associated with higher risk of post-stroke NCD at 18 and 36 months. In conclusion, a younger appearing brain is associated with a lower risk of post-stroke NCD.

Neuroimaging markers of dual impairment in cognition and physical performance following stroke: The Nor-COAST study.

Background: Cognitive decline and decline in physical performance are common after stroke. Concurrent impairments in the two domains are reported to give increased risk of dementia and functional decline. The concept of dual impairment of physical performance and cognition after stroke is poorly investigated. Clinically accessible imaging markers of stroke and pre-existing brain pathology might help identify patients at risk. Objective: The primary aim of this study was to investigate to which extent pre-stroke cerebral pathology was associated with dual impairment in cognition and physical performance at time of stroke. Secondary aims were to examine whether white matter hyperintensities, medial temporal lobe atrophy, and stroke lesion volume and location were associated with dual impairment. Methods: Participants from the Norwegian Cognitive Impairment After Stroke (Nor-COAST) study with available MRI data at baseline were included in this cross-sectional study. Logistic regression analyses were conducted, with impairment status (no impairment, impaired cognition, impaired physical performance, and dual impairment) as the dependent variable and MRI markers as covariates. Pre-existing brain pathologies were classified into neurodegenerative, cerebrovascular, or mixed pathology. In addition, white matter hyperintensities and medial temporal lobe atrophy were included as independent covariates. Stroke volume and location were also ascertained from study-specific MRI scans. Results: Participants' (n = 348) mean (SD) age was 72.3 (11.3) years; 148 (42.5%) were women. Participants with dual impairment (n = 99) were significantly older, had experienced a more severe stroke, and had a higher comorbidity burden and poorer pre-stroke function. Stroke lesion volume (odds ratio 1.03, 95%, confidence interval 1.00 to 1.05, p = 0.035), but not stroke location or pre-existing brain pathology, was associated with dual impairment, after adjusting for age and sex. Conclusion: In this large cohort of stroke survivors having suffered mainly mild to moderate stroke, stroke lesion volume-but not pre-existing brain pathology-was associated with dual impairment early after stroke, confirming the role of stroke severity in functional decline.

Cohort profile: the Norwegian Registry of Persons Assessed for Cognitive Symptoms (NorCog) - a national research and quality registry with a biomaterial collection.

PURPOSE: The Norwegian Registry of Persons Assessed for Cognitive Symptoms (NorCog) was established to harmonise and improve the quality of diagnostic practice across clinics assessing persons with cognitive symptoms in Norwegian specialist healthcare units and to establish a large research cohort with extensive clinical data. PARTICIPANTS: The registry recruits patients who are referred for assessment of cognitive symptoms and suspected dementia at outpatient clinics in Norwegian specialist healthcare units. In total, 18 120 patients have been included in NorCog during the period of 2009-2021. The average age at inclusion was 73.7 years. About half of the patients (46%) were diagnosed with dementia at the baseline assessment, 35% with mild cognitive impairment and 13% with no or subjective cognitive impairment; 7% received other specified diagnoses such as mood disorders. FINDINGS TO DATE: All patients have a detailed baseline characterisation involving lifestyle and demographic variables; activities of daily living; caregiver situation; medical history; medication; psychiatric, physical and neurological examinations; neurocognitive testing; blood laboratory work-up; and structural or functional brain imaging. Diagnoses are set according to standardised diagnostic criteria. The research biobank stores DNA and blood samples from 4000 patients as well as cerebrospinal fluid from 800 patients. Data from NorCog have been used in a wide range of research projects evaluating and validating dementia-related assessment tools, and identifying patient characteristics, symptoms, functioning and needs, as well as caregiver burden and requirement of available resources. FUTURE PLANS: The finish date of NorCog was originally in 2029. In 2021, the registry's legal basis was reformalised and NorCog got approval to collect and keep data for as long as is necessary to achieve the purpose of the registry. In 2022, the registry underwent major changes. Paper-based data collection was replaced with digital registration, and the number of variables collected was reduced. Future plans involve expanding the registry to include patients from primary care centres.